title: Molecular modeling of interleukin-8 receptor beta and analysis of the receptor-ligand interaction.
abstract: A structural model of interleukin-8 receptor type beta (IL-8R-beta) was constructed based on the structure of bacteriorhodopsin. High temperature molecular dynamics simulations were performed to search the possible conformations of loop regions in IL-8R-beta which recognize the ligand. The crystal structure of interleukin 8 (IL-8) was used as a geometric constraint of the extracellular loop regions of IL-8R-beta in the conformational search. 500 complex structures were extracted from the dynamics trajectory and five plausible models were selected based on the binding energy and known experimental data. To study further the interaction between IL-8R-beta and its ligands, the complex of IL-8R-beta and platelet factor 4 (PF4) C-terminal peptide was also modeled by molecular dynamics simulations. From these models, the N-terminus, extracellular domain 3 and extracellular domain 4 of IL-8R-beta were found to be important for ligand binding. Key residues of these regions involved in ligand binding were characterized. These models provide insight into the structural basis of biological activity of IL-8 and PF4 and may guide the design of potential therapeutic agents targeting IL-8 receptors. Furthermore, the approach developed from this study may have implications for the understanding of other chemokine receptor-ligand interactions that have been recently suggested to be involved in HIV infection.
authors.affiliation: Kimmel Cancer Institute, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Luo
authors.forename: D J
authors.initials: DJ
authors.lastname: Butcher
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000138:chemical synthesis; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis; D002942:Circular Dichroism; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D015497:HIV-1; D016209:Interleukin-8 / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010978:Platelet Factor 4 / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011565:Psoriasis / Q000188:drug therapy; D019707:Receptors, Chemokine / Q000737:chemistry* / Q000378:metabolism; D018123:Receptors, Interleukin / Q000737:chemistry* / Q000378:metabolism; D023063:Receptors, Interleukin-8B
chemical_list: D019380:Anti-HIV Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016209:Interleukin-8; D008024:Ligands; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D023063:Receptors, Interleukin-8B; D010978:Platelet Factor 4